CN1310915C - Pyrido(2,1-a)isoquinoline derivatives as DPP-IV inhibitors - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein R1, R2, R3, R4, R5 and R6 are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, particularly non-insulin dependent diabetes mellitus, and impaired glucose tolerance.

Description

Pyrido(2,1-a)isoquinoline derivatives as DPP-IV inhibitors

  New pyrido[2,1-a]isoquinoline derivatives

The present invention relates to novel pyrido[2,1-a]isoquinoline derivatives, a process for their preparation and their use as medicines. The present invention particularly relates to compounds of general formula (I) and pharmaceutically acceptable salts thereof:

in

^R is lower alkyl, aryl, heteroaryl, or lower alkyl substituted by cycloalkyl, aryl, or heteroaryl;

R ² , R ³ , and R ⁴ are each independently hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy or lower alkenyl, wherein lower alkyl, lower alkoxy and lower alkenyl can optionally be replaced by lower Alkoxycarbonyl, aryl or heterocyclyl substitution.

^R is hydrogen, fluorine, lower alkyl or aryl;

^R is hydrogen, lower alkyl or hydroxy-lower alkyl; or

R ⁵ and R ⁶ form a 5- or 6-membered saturated carbocyclic ring together with the carbon atoms to which they are attached;

R ⁷ is hydrogen, fluorine or lower alkyl.

Dipeptidyl peptidase IV (EC.3.4.14.5, hereinafter abbreviated as DPP-IV) is involved in regulating the activity of several hormones. DPP-IV is particularly potent and rapidly degrades glucagon-like peptide 1 (GLP-1), one of the most potent stimulators of insulin production and secretion. Inhibition of DPP-IV potentiates the action of endogenous GLP-1 and produces higher plasma insulin concentrations. In patients with impaired glucose tolerance and type 2 diabetes, higher plasma insulin concentrations can attenuate dangerous hyperglycemia and thereby reduce the risk of tissue damage. Therefore, DPP-IV inhibitors have been suggested as drug candidates for the treatment of impaired glucose tolerance and type 2 diabetes (eg VilHauer, W098/19998). Buzas et al in Lab.Chim.Org.V, Fac.Sci., Orleans in Fr.Chim.Ther.(1992), 7(5), 404-7 describe the synthesis of the compounds of the following examples 41 and 42 , but does not disclose any medical applications.

We have discovered new DPP-IV inhibitors that are extremely effective in lowering blood glucose levels. The compounds of the invention are therefore useful in the treatment and/or prevention of diabetes, especially non-insulin-dependent diabetes and/or impaired glucose tolerance and other diseases in which enhancing the action of peptides normally inactivated by DPP-IV yields a therapeutic benefit. Surprisingly, the compounds of the present invention can also be used for the treatment and/or prevention of bowel disease (bowl disease), ulcerative colitis (Colitis Ulcerosa), Crohn's disease (Morbus Crohn), obesity and/or metabolic syndrome sign. Furthermore, the compounds of the invention can be used as diuretics and for the treatment and/or prevention of hypertension. Surprisingly, the compounds of the present invention exhibit improved therapeutic and pharmacological properties, such as pharmacokinetics and bioavailability, compared to other DPP-IV inhibitors known in the art.

Unless otherwise stated, the following definitions are set forth to explain and define the meaning and scope of various terms used herein to describe the invention.

In this specification, the term "lower" is used to refer to a group consisting of 1-6, preferably 1-4 carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably chlorine.

The term "alkyl", alone or in combination with other groups, refers to a branched or straight chain monovalent saturated Aliphatic hydrocarbon group.

The term "lower alkyl", alone or in combination with other groups, refers to a branched or straight chain monovalent alkyl group of 1-6 carbon atoms, preferably 1-4 carbon atoms. The term is further denoted by terms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2 -Ethylbutyl and the like are typical.

The term "cycloalkyl" refers to a monovalent carbocyclic group of 3 to 6 carbon atoms. The term is further typified by cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with cyclopropyl being preferred.

The term "alkoxy" refers to the group R'-O-, where R' is alkyl. The term "lower alkoxy" refers to the group R'-O-, where R' is lower alkyl. Examples of lower alkoxy are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, particularly preferably methoxy.

The term "lower alkoxycarbonyl" refers to the group R'-O-C(O)-, where R' is lower alkyl.

The term "heterocyclyl" refers to a 5- or 6-membered aromatic or saturated N-heterocyclic residue which may optionally contain another nitrogen or oxygen atom, such as imidazolyl, pyrazolyl, thiazolyl, phenyl , pyridyl, pyrimidyl, morpholino, piperazino, piperidino or pyrrolidino, preferably pyridyl, thiazolyl or morpholino. Such heterocycles may be optionally mono-, di-, or tri-substituted independently with lower alkyl, lower alkoxy, halogen, cyano, azido, amino, di-lower alkylamino, or hydroxy. Preferred substituents are lower alkyl, preferably methyl.

The term "aryl" refers to an aromatic monovalent mono- or polycarbocyclic group, such as phenyl or naphthyl, preferably phenyl, which may be optionally independently replaced by lower alkyl, lower alkoxy, halogen, Cyano, azido, amino, di-lower alkylamino or hydroxy monosubstituted, disubstituted or trisubstituted.

The term "heteroaryl" refers to a 5- or 6-membered unsaturated aromatic monovalent ring containing 1-3, preferably 1 or 2 heteroatoms independently selected from nitrogen, sulfur and oxygen, preferably nitrogen group. Examples of heteroaryl residues are pyrrolyl, pyridyl and pyrimidinyl, preferably pyrrolyl and pyridyl. Said heteroaryl residues may be independently mono-, di- or tri-substituted with halogen, amino, perfluoro-lower alkyl, lower alkyl or lower alkoxy. The term "pharmaceutically acceptable salt" includes salts formed by compounds of general formula (I) and non-toxic inorganic or organic acids to living organisms, such as hydrochloric acid, hydrobromic acid, nitric acid , sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, salicylic acid, p-toluenesulfonic acid, etc. Preferred salts with acids are formate, maleate, citrate, hydrochloride, hydrobromide and methanesulfonate, the hydrochloride being particularly preferred.

In one embodiment, the present invention relates to compounds of general formula (I) as described above, and pharmaceutically acceptable salts thereof, wherein ^R is lower alkyl, aryl, or lower alkyl substituted by cycloalkyl or aryl R ² , R ³ , R ⁴ are each independently hydrogen, hydroxyl, lower alkyl, lower alkoxy or lower alkenyl, wherein lower alkyl, lower alkoxy and lower alkenyl can be optionally replaced by lower Substituted by alkoxycarbonyl, aryl or heterocyclic; R ⁵ and R ⁶ are each independently hydrogen, lower alkyl, aryl or form a 5- or 6-membered saturated carbocyclic ring together with the carbon atoms they are connected to.

In another embodiment the present invention relates to compounds of general formula (I) as described above, wherein R ¹ is lower alkyl, phenyl or cycloalkyl-lower alkyl; R ² , R ³ , R ⁴ are independently is hydrogen, hydroxy, lower alkoxy or lower alkoxy substituted by aryl, heterocyclic or lower alkoxycarbonyl. Preferably, the aryl residues on R ² , R ³ , R ⁴ are phenyl or phenyl substituted by di-lower alkylamino or cyano. Preferably, the aryl residues on R ² , R ³ , R ⁴ are morpholino, pyridyl, thiazolyl or thiazolyl substituted by lower alkyl. Preferably, the lower alkoxycarbonyl residues on R ² , R ³ , R ⁴ are ethoxycarbonylmethoxy.

In another embodiment the present invention relates to compounds of general formula (I) as described above, wherein ^R is lower alkyl, phenyl, phenyl substituted by lower alkyl or lower alkoxy or ^R is hetero Aryl, such as pyrrolyl and pyridyl or cycloalkyl-lower alkyl; R ² , R ³ , R ⁴ are each independently hydrogen, hydroxyl, lower alkoxy or aryl, heterocyclyl or lower alkoxycarbonyl Substituted lower alkoxy; R ⁵ is hydrogen, lower alkyl or phenyl, which is monosubstituted or disubstituted by lower alkyl, lower alkoxy or halogen; R ⁶ is hydrogen, lower alkyl or hydroxy-lower alkane or R ⁵ and R ⁶ together with the carbon atoms to which they are attached form a 5- or 6-membered saturated carbocyclic ring; and R ⁷ is hydrogen or lower alkyl.

In one embodiment, the residue ^R1 is lower alkyl or lower alkyl substituted by cycloalkyl, preferably cyclopropyl. Preferred lower alkyl residues ^R are n-propyl, n-butyl, isobutyl, 3-methylbutyl and 2-ethylbutyl, most preferably n-propyl, n-butyl and 3-methylbutyl . A preferred lower alkyl substituted by cycloalkyl is cyclopropylmethyl.

In another embodiment ^R1 is aryl, preferably phenyl. The aryl residue R ¹ may independently be mono-, di- or tri-substituted with lower alkyl, lower alkoxy or hydroxy, preferably with lower alkyl or lower alkoxy. Preferably the aryl residue R ¹ is unsubstituted.

In another embodiment, R ¹ is a heteroaryl residue selected from pyridyl, pyrimidinyl and pyrrolyl. Preferred heteroaryl residues ^R1 are pyridyl or pyrrolyl. Said heteroaryl residue R ¹ may be independently mono-, di- or tri-substituted with lower alkyl, lower alkoxy or hydroxyl, preferably with lower alkyl or lower alkoxy. Preferably the heteroaryl residue R ¹ is unsubstituted.

Most preferably ^R1 is lower alkyl, preferably n-butyl or unsubstituted phenyl.

In a preferred embodiment, the residue ^R2 is lower alkoxy, preferably methoxy, hydrogen or hydroxy. Most preferably the residue ^R2 is methoxy.

In another preferred embodiment, the residue ^R is: lower alkoxy, preferably methoxy, ethoxy, propoxy, n-butoxy and isobutoxy; hydrogen; hydroxy; or lower alkoxy Oxy, preferably methoxy or ethoxy, which are substituted by aryl, heterocyclyl or lower alkoxycarbonyl. Preferred aryl substituents on ^R3 are unsubstituted phenyl or phenyl monosubstituted with di-lower alkylamino, preferably dimethylamino, or cyano. Most preferably the aryl substituent on ^R3 is unsubstituted phenyl.

More preferably the residue ^R3 is lower alkoxy, preferably methoxy, hydrogen or hydroxy. Most preferably the residue ^R3 is methoxy or hydroxy, particularly preferably methoxy.

In another preferred embodiment, the residue ^R4 is lower alkoxy, preferably methoxy, hydrogen or hydroxy. Most preferably residue ^R4 is hydrogen.

In one embodiment, ^R5 is hydrogen, lower alkyl, preferably methyl, or aryl. Preferably the aryl residue ^R5 is unsubstituted phenyl or phenyl mono-, di- or trisubstituted independently by lower alkyl, lower alkoxy or halogen. Most preferably the aryl residue ^R5 is unsubstituted phenyl.

In another embodiment, ^R6 is hydrogen, lower alkyl, preferably methyl, or hydroxy-lower alkyl, preferably 2-hydroxy-ethyl. Preferably ^R6 is hydrogen.

In another embodiment, ^R5 and ^R6 are hydrogen or together with the carbon atom to which they are attached form a 6 membered saturated carbocyclic ring.

In one embodiment, ^R7 is hydrogen; in another embodiment, ^R7 is lower alkyl, preferably methyl.

The compounds of the general formula (I) represent preferred embodiments of the invention and the pharmaceutically acceptable salts of the compounds of the general formula (I) also respectively represent preferred embodiments of the invention.

Preferred compounds of general general formula (I) are those selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:

rac-9,10-dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine ;

rac-9,10-dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]iso Quinolin-2α-ylamine;

rac-3β-cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2β - Base amine;

rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f] Phenanthridine-8β-ylamine;

rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine Dihydrochloride (chlorohydrate (1:2));

rac-9,10-dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine Dihydrochloride;

rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f] Phenanthridine-8β-ylamine dihydrochloride;

rac-2β-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol Dihydrochloride;

rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol Dihydrochloride;

rac-2β-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol ;

rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol ;and

rac-9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine .

Other preferred compounds of general general formula (I) are those selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:

rac-9,10-dimethoxy-3β-pyrrol-1-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α - Base amine;

rac-9,10-dimethoxy-3β-p-tolyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-yl amine;

rac-9,10-dimethoxy-3β-p-tolyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl amine;

rac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1- a] isoquinolin-2β-ylamine dihydrochloride;

rac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1- a] isoquinolin-2α-ylamine dihydrochloride;

rac-9,10-dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a] Isoquinolin-2β-ylamine dihydrochloride;

rac-9,10-dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a] Isoquinolin-2α-ylamine dihydrochloride;

rac-9,10-dimethoxy-3β-pyridine-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine di Hydrochloride,

rac-9,10-dimethoxy-3β-pyridine-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine di Hydrochloride;

rac-4-(2β-amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]iso Quinoline-7β-yl)-phenol;

rac-3β-butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline -2-ylamine;

rac-3β-butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1 -a] isoquinolin-2α-ylamine;

rac-3β-butyl-7-α-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2, 1-a] isoquinolin-2α-ylamine;

rac-3β-butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyridine And [2,1-a] isoquinolin-2α-ylamine;

rac-3β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a] Isoquinolin-2α-ylamine;

rac-3β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a] Isoquinolin-2β-ylamine;

rac-7β-butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2-f] Phenanthridine-8β-ylamine;

rac-7β-butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2-f] Phenanthridine-8α-ylamine;

rac-3β-butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ-hexa Hydrogen-2H-pyrido[2,1-a]isoquinolin-2-ylamine;

rac-7β-butyl-11,12-dimethoxy-13b-methyl-2,3,4,4aβ,6,7,8,9,9a,13b-decahydro-1H-pyrido[1 , 2-f] phenanthridine-8β-ylamine;

rac-9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine ;

rac-9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine ;

9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine;

9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine;

9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine;

9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine;

(6S)-(2-Amino-3-butyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]iso Quinolin-6-yl)-methanol;

rac-4-(2β-amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]iso Quinolin-7-yl)-phenol hydrochloride;

rac-4-(2β-amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]iso Quinoline-7β-yl)-phenol hydrochloride;

rac-3β-butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline -2-ylamine hydrochloride;

rac-3β-butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1 -a] isoquinolin-2α-ylamine hydrochloride;

rac-3β-butyl-7α-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1 -a] isoquinolin-2α-ylamine hydrochloride;

rac-3β-butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyridine And[2,1-a]isoquinolin-2α-ylamine hydrochloride;

rac-3α-butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyridine And[2,1-a]isoquinolin-2β-ylamine hydrochloride;

rac-3β-butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyridine And[2,1-a]isoquinolin-2β-ylamine hydrochloride;

rac-3β-butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyridine And[2,1-a]isoquinolin-2α-ylamine hydrochloride;

rac-3β-butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβhexahydro-2H-pyrido[2, 1-a] isoquinolin-2α-ylamine hydrochloride;

rac-3β-butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2 , 1-a] isoquinolin-2β-ylamine hydrochloride;

rac-3β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a] Isoquinolin-2α-ylamine hydrochloride;

rac-3β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a] Isoquinolin-2β-ylamine hydrochloride;

rac-7β-butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2-f] Phenanthridine-8β-ylamine hydrochloride;

rac-7β-butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα13bβ-decahydro-1H-pyrido[1,2-f]phenanthridine -8α-ylamine hydrochloride;

rac-3β-butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ-hexa Hydrogen-2H-pyrido[2,1-a]isoquinolin-2-ylamine hydrochloride.

Other preferred compounds of general general formula (I) are those selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:

rac-9,10-dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]iso Quinolin-2α-ylamine;

rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f] Phenanthridine-8β-ylamine;

rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine Dihydrochloride;

rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f] Phenanthridine-8β-ylamine dihydrochloride;

rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol Dihydrochloride;

rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol ;and

rac-9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine .

Particularly preferred compounds of general general formula (I) are those selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:

rac-9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine ;

rac-9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine ;

rac-9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine ;

9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine;

9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine;

9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine; and

9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine.

The most preferred compounds of general general formula (I) are those selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:

9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine;

9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine;

9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine; and

9,10-Diphenoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine.

The compounds of the general formula (I) may bear one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers or as racemates. The present invention includes all such forms.

It is understood that functional groups of the compounds of general formula (I) of the present invention may be derivatized to obtain derivatives which can be converted back to the parent compound in vivo.

The present invention also relates to the preparation method of the compound of general formula (I) as described above, the method comprises the following steps:

reducing the oxime of general formula (II);

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above;

It is then optionally converted into a pharmaceutically acceptable salt thereof.

The oximes of formula II above can be hydrogenated according to methods well known in the art. For example, the reaction can be carried out at a temperature of from about 20°C to about 80°C in an inert solvent such as ethanol in the presence of a catalyst such as Raney nickel, platinum or palladium.

The hydroxyl group on the compound of formula II may exist in protected form, for example as benzyl ether. Such protecting groups can be removed according to methods well known in the art, for example, in the case of benzyl ethers, by catalytic hydrogenation.

The oximes of the general formula II are known in the art or can be prepared from ketones of the general formula III as starting materials by methods known and typical in the art or by methods analogous thereto.

Compounds of general formula (III) can be prepared by the following reactions:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above;

Make the compound of general formula (IV) react with the compound of general formula (V) or the compound of general formula (VI), wherein the structural formula of general formula (IV) compound is as follows:

wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above;

Wherein the structural formula of general formula (V) is as follows:

Wherein R ¹ is as defined above;

Wherein the structural formula of general formula (VI) is as follows:

wherein R ¹ is as defined above.

The compound of general formula (IV) is known in the art or can be prepared by oxidation of the compound of general formula (VIII) according to known and typical methods or methods similar thereto, wherein the structural formula of general formula VIII is as follows :

wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above.

On the other hand, the compound of general formula (VII) can be reacted with alcohol in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate, wherein the structural formula of the compound of general formula (VII) is as follows:

wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above and P represents an amino protecting group;

Wherein the structural formula of said alcohol is as follows:

R-OH

Wherein R is lower alkyl substituted by aryl, heterocyclyl or lower alkoxycarbonyl;

Subsequent deprotection.

On the other hand, a compound of general formula (III) wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above and R ¹ is hydrogen (R ¹ =H) can be combined with Aryl Halides Heteroaryl Halides

R-X

reaction to prepare compounds of general formula (III) wherein ^R is aryl or heteroaryl, wherein said wherein R is aryl or heteroaryl and X is chloride, bromide, iodide or trifluoromethane Sulfonate ion, the reaction is at a moderate temperature of 20-100°C with a palladium catalyst such as palladium acetate or tetrakis-triphenylphosphine-palladium complex, a ligand such as tri-tert-butylphosphine or other phosphines and a base such as Sodium tert-butoxide exists in an inert solvent such as tetrahydrofuran (with JMFox, X.Huang, A.Chieffi, SLBuchwald. in "Journal of the American Chemical Society" (J.Am.Chem.Soc.) 2000, 122, 1360- 1370. and similar to the method described by M. Kawatsura and JF Hartwig in J. Am. Chem. Soc. 1999, 121, 1473-1478).

Preferred amino-protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) and 9-fluorenylmethoxycarbonyl (Fmoc), particularly preferably tert-butoxycarbonyl (Boc). Deprotection can be performed by methods known in the art.

The invention further relates to compounds of general formula (I) as described above, their preparation as described above.

As mentioned above, the compound of the general formula (I) of the present invention can be used as a drug for the treatment and/or prevention of diseases related to DPP-IV, such as diabetes mellitus, especially non-insulin-dependent diabetes mellitus, impaired glucose tolerance , bowel disease (bowl disease), ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome, preferably non-insulin dependent diabetes and/or impaired glucose tolerance. Furthermore, the compounds of the invention can be used as diuretics or for the treatment and/or prevention of hypertension.

The present invention thus also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.

Furthermore, the invention relates to the use as a therapeutically active substance, in particular as a therapeutically active substance for the treatment and/or prophylaxis of diseases associated with DPP-IV, such as diabetes mellitus, in particular non-insulin-dependent diabetes mellitus, impaired glucose tolerance , bowel disease (bowl disease), ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome; preferably for use as a therapeutically active substance for the treatment and/or prophylaxis of non-insulin-dependent diabetes mellitus and/or impaired glucose tolerance A compound as defined above. The present invention further relates to the use of compounds as defined above as diuretics or as therapeutically active substances for the treatment and/or prevention of hypertension.

In another embodiment the present invention relates to methods for the treatment and/or prevention of diseases associated with DPP-IV, such as diabetes mellitus, especially non-insulin-dependent diabetes mellitus, impaired glucose tolerance, bowel disease (bowl disease), Ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome; preferably a method for the treatment and/or prevention of non-insulin-dependent diabetes mellitus and/or impaired glucose tolerance comprising administering to humans or animals The steps of the compound. The invention further relates to a method of treatment and/or prevention as defined above, wherein said disease is hypertension or wherein diuretics have a beneficial effect.

The present invention further relates to the use of compounds as defined above in the treatment and/or prevention of diseases associated with DPP-IV, such as diabetes mellitus, especially non-insulin-dependent diabetes mellitus, impaired glucose tolerance, bowel disease (bowl disease), ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome; preferably for use in the treatment and/or prevention of non-insulin-dependent diabetes and/or impaired glucose tolerance. The invention also relates to the use as defined above or as a diuretic, wherein said disease is hypertension.

Furthermore, the present invention relates to the use of a compound as defined above for the preparation of a medicament for the treatment and/or prevention of diseases associated with DPP-IV, such as diabetes mellitus, in particular non-insulin-dependent diabetes mellitus, glucose tolerance Lowering, bowel disease (bowl disease), ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome; preferably in the manufacture of a medicament for the treatment and/or prevention of non-insulin-dependent diabetes and/or impaired glucose tolerance in the application. Such drugs include compounds as defined above. The invention also relates to the use as defined above or for the manufacture of a diuretic, wherein said disease is hypertension.

In the methods and uses as defined above, the following diseases relate to preferred embodiments: diabetes mellitus, especially non-insulin-dependent diabetes mellitus; impaired glucose tolerance; obesity and/or metabolic syndrome, preferably non-insulin-dependent diabetes mellitus and/or glucose Reduced stamina.

The compounds of general formula (I) can be prepared by the methods given below, by the methods given in the examples or by analogous methods. Suitable reaction conditions used in the individual reaction steps are well known to those skilled in the art. Starting materials are commercially available or can be prepared by methods analogous to those given below or in the Examples or by methods well known in the art.

The following tests were carried out in order to determine the activity of the compounds of general formula I.

DPP-IV inhibitor activity was tested with native human DPP-IV or recombinant human DPP-IV derived from human plasma pools. Human citrated plasma from various donors was collected, filtered under sterile conditions through a 0.2 micron membrane and 1 ml aliquots were quenched and stored at -120°C until use. 5-10 μl of human plasma in the DPP-IV chromogenic assay and 1.0 μl of human plasma in the fluorescent assay, for a total of 100 μl assay volumes were used as enzyme sources. The cDNA of amino acid sequence 31--766 of human DPP-IV restricted by the N-terminal and transmembrane domains was cloned into Pichia pastoris. Human DPP-IV is expressed and purified from the culture medium using conventional column chromatography including size exclusion and anion and cation chromatography. The final Coomassie blue SDS-PAGE purity of the enzyme preparation was >95%. 20 ng rec.-h DPP-IV in the DPP-IV chromogenic assay and 2 ng rec-hDPP-IV in the fluorescent assay, in a total of 100 μl assay volume were used as enzyme sources.

In the fluorescence assay, Ala-Pro-7-amido-4-trifluoromethylcoumarin (Calbiochem No 125510) was used as substrate. Stock solutions of 20 mM in 10% DMF/ _H2O were stored at -20°C until use. In _IC50 determinations, a final substrate concentration of 50 μM was used. In experiments to determine kinetic parameters such as _Km , _Vmax , _K1 , substrate concentrations were varied between 10 [mu]M-500 [mu]M.

In the colorimetric assay, H-Ala-Pro-pNA.HCl (Bachem L-1115) was used as substrate. Stock solutions of 10 mM in 10% MeOH/ _H2O were stored at -20°C until use. In the _IC50 determination, a final substrate concentration of 200 μM was used. In experiments to determine kinetic parameters such as Km, Vmax, Ki, the substrate concentration was varied between 100 [mu]M-2000 [mu]M.

Use a Perkin Elmer luminescence spectrometer LS 50B to detect fluorescence at an excitation wavelength of 400nm and an emission wavelength of 505nm, and detect once every 15 seconds for 10-30 minutes. Starting rate constants were calculated by best-fit linear regression.

The absorbance of pNA released from the chromogenic substrate was measured at 405nM with a Packard Spectracount every 2 minutes for 30-120 minutes. Starting rate constants were calculated by best-fit linear regression.

DPP-IV activity assays were performed in 96-well plates with a total assay volume of 100 ul at 37°C. Assay buffer consisted of 50 mM Tris/HCl pH 7.8 containing 0.1 mg/ml BSA and 100 mM NaCl. Test compounds were dissolved in 100% DMSO and diluted to desired concentrations with 10% DMSO/ _H2O . The final DMSO concentration in this assay was 1% (v/v). At this concentration, DMSO caused <5% enzyme inactivation. Compounds were pre-incubated with the enzyme (10 min at 37°C) and not pre-incubated with the enzyme. Enzyme reactions are initiated by application of substrate followed by immediate mixing.

_IC50 determinations for test compounds were calculated by non-linear best fit regression of DPP-IV inhibition produced by at least 5 different compound concentrations. Kinetic parameters of the enzyme reaction are calculated at at least 5 different substrate concentrations and at least 5 different test compound concentrations.

Preferred compounds of the invention exhibit _IC50 values of 1 nM-10 uM, more preferably 1-100 nM, as shown in the table below. Example _IC50 [μM] 5 0.57 17 0.14 20 0.52 36 0.16 39 0.62 43b 0.34 44 0.22

The compounds of general formula I and/or their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical preparations for enteral, parenteral or topical administration. For example, they can be administered orally, such as in the form of tablets, coated tablets, lozenges, hard and soft capsules, solutions, emulsions or suspensions; rectally, such as in the form of suppositories; parenterally Orally, for example in the form of injection or infusion or topically, for example in the form of ointments, creams or oils. Oral administration is preferred.

The pharmaceutical preparation can be produced in any manner known to those skilled in the art through the following steps: the compound of the general formula I and/or its pharmaceutically acceptable salt is optionally mixed with other therapeutically valuable substances Galenical dosage forms are mixed together with suitable nontoxic, inert, therapeutically compatible solid or liquid carrier substances and, if desired, customary pharmaceutical auxiliaries.

Suitable carrier substances are not only inorganic carrier substances but also organic carrier substances. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier substances for tablets, coated tablets, dragees and hard capsules. Suitable carrier substances for soft capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active ingredient, no carrier may be required in the case of soft capsules). Suitable carrier substances for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier substances for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier substances for suppositories are, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols. Suitable carrier substances for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffin, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents, thickeners, flavourings, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.

The amount of the compound of general formula I may vary within wide limits, depending on the disease under control, the age and individual condition of the patient and the mode of administration and should of course be adapted to the individual needs in each particular case. For adult patients, a daily dosage of about 1-1000 mg, especially about 1-100 mg, comes into consideration. Depending on the severity of the disease and the exact pharmacokinetic profile, the compound can be administered in one or several daily dosage units, eg 1-3 dosage units.

Said pharmaceutical preparations suitably contain about 1-500 mg, preferably 1-100 mg, of the compound of general formula I.

The following examples are used to explain the present invention more specifically. However, they do not limit the scope of the invention in any way.

Example

abbreviation:

MS = mass spectrometry; ISP = ion spray (cation), equivalent to ESI (electrospray, cation); b.p. = boiling point; m.p. = melting point; aq. = aqueous; r.t. = room temperature.

Example 1

rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine and rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl amine

(i) Treat 6.8 g of 3,4-dihydro-6,7-dimethoxy-isoquinoline with 11.4 g of (2-acetylhexyl) trimethylammonium iodide and dissolve the resulting solution in 70 ml of ethanol and Heat at reflux for 1.5 hours. The reaction mixture was cooled and treated with a solution of 6.8 g potassium hydroxide dissolved in 70 ml water. Ethanol was evaporated and the aqueous solution was extracted three times with 80 ml of dichloromethane. The combined organic solutions were treated with anhydrous sodium sulfate and evaporated. The solid red residue was purified by chromatography (silica gel, hexane/ethyl acetate 4:1) and crystallized from isopropyl ether. Obtained 7.0 g rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one , m.p. = 117°C.

(ii) 5.5g of hydroxylamine hydrochloride was dissolved in 50ml of water and 20ml of ethanol with 7.27ml of N sodium hydroxide solution, and the resulting solution was alkaline (pH 9) and added 3.35grac-3β-butyl-9, 10 - A solution obtained by dissolving dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one in 50 ml of ethanol. The reaction mixture was stirred at 45°C for 45 minutes, concentrated by half and then cooled to 0°C. The precipitated product was filtered and washed with ethanol/water (1:1) followed by water. 3.26 grac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one oxime was obtained , m.p. = 143-145°C.

(iii) 1.5 grac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1- a] A suspension obtained by dissolving isoquinolin-2-one oxime in 40 ml ethanol and 40 ml water was added dropwise to 4.935 ml 32% aqueous sodium hydroxide solution. The mixture was stirred vigorously at room temperature for 4 hours, then filtered and washed with ethanol/water (1:1). The filtrate was extracted twice with dichloromethane and the combined organic solutions were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The solid residue was purified by chromatography (silica gel, dichloromethane-methanol/25% ammonium hydroxide (0-16%)). Obtained: (a) 0.38 g rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]iso Quinolin-2β-ylamine, as resin, MS(ISP) 319.4 (M+H) ⁺ and (b) 0.45g rac-3β-butyl-9,10-dimethoxy-1,3,4, 6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine as a resin, MS (ISP) 319.4 (M+H) ⁺ .

Example 2-18

The following compounds were prepared in a similar manner to Example 1:

2.rac-9,10-dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2β- Base amine, resin, MS(ISP) 305.3(M+H) ⁺ .

3.rac-9,10-dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α- Base amine, resin, MS(ISP) 305.3(M+H) ⁺ .

4.rac-9,10-dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] Isoquinolin-2β-ylamine as a resin, MS (ISP) 333.3 (M+H) ⁺ .

5.rac-9,10-dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] Isoquinolin-2α-ylamine as a resin, MS (ISP) 333.3 (M+H) ⁺ .

6.rac-3β-(2-ethyl-butyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] Isoquinolin-2β-ylamine as a resin, MS (ISP) 347.5 (M+H) ⁺ .

7. rac-3β-(2-ethyl-butyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] Isoquinolin-2α-ylamine as a resin, MS (ISP) 347.5 (M+H) ⁺ .

8.rac-3β-cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline -2β-ylamine, as a resin, MS (ISP) 317.3 (M+H) ⁺ .

9.rac-3β-cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline -2α-ylamine, as a resin, MS (ISP) 317.3 (M+H) ⁺ .

10. rac-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine, It is a resin, MS (ISP) 347.5 (M+H) ⁺ .

11. rac-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine as an oil, MS ( ISP) 359.2(M+H) ⁺ .

12. rac-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine as an oil, MS ( ISP) 359.2(M+H) ⁺ .

13.rac-3β-butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α- Base amine, resin, MS (ISP) 319.5 (M+H) ⁺ .

14. rac-3β-butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α- Amylamine, MS (ISP) 319.5 (M+H) ⁺ .

15. rac-2β-amino-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-10 - Alcohol as an oil, MS (ISP) 305.3 (M+H) ⁺ .

16. rac-2α-amino-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-10 - Alcohol, MS (ISP) 305.3 (M+H) ⁺ .

17.rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2- f] Phenanthridine-8β-ylamine as a solid, MS (ISP) 373.5 (M+H) ⁺ .

18.rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2- f] Phenanthridine-8α-ylamine, an oil, MS (ISP) 373.5 (M+H) ⁺ .

Experiments not previously described can be prepared according to the procedure described below or analogous thereto.

Educts used in Examples 1-18 (compounds of general formula II and III).

Oxime derivatives (compounds of general formula II)

According to the method used to prepare rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1- a] Isoquinolin-2-one oxime similar steps prepare the following compounds:

rac-9,10-dimethoxy-3-β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]iso Quinolin-2-one oxime, MS (ISP): 347.4 (M+H) ⁺ .

rac-3β-(2-ethyl-butyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinoline -2-Ketoxime, MS (ISP): 361.3 (M+H) ⁺ .

rac-3β-cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one Oxime, m.p. = 156-158°C.

rac-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one oxime, m.p.=155- 159°C.

rac-7β-butyl-1,3,4,6,7,13bβ-hexahydro-pyrido[1,2-a]isoquinolin-2-one oxime, m.p.=140-144°C.

rac-3β-butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one oxime, m.p. = 148-150°C.

rac-3β-butyl-10-hydroxy-9-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one oxime, m.p. = 118-120°C.

rac-7-butyl-11,12-dimethoxy-1,2,3,4,4a,6,7,9,9a,13b-decahydro-pyrido[1,2-f]phenanthridine -8-Ketoxime, m.p.=122-125°C.

Ketone derivatives (compounds of general formula III)

According to the method used to prepare rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1- a] isoquinolin-2-ketone similar steps prepare the following compounds:

rac-3β-butyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one, m.p.=95°C.

rac-3β-butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one, m.p.= 89-91°C.

rac-3β-butyl-10-hydroxy-9-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one, m.p. = 136°C.

rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f] Phenanthridin-8-one, m.p. = 157°C.

rac-3β-cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one

To the solution obtained by dissolving 3g of 3,4-dihydro-6,7-dimethoxy-isoquinoline in 10ml of ethanol, add 2.45g of 3-[(dimethylamino)methyl]-4-cyclopropane The resulting solution was diethyl-2-butanone and the mixture was stirred at room temperature for 18 hours. The solid was filtered off, washed with water and recrystallized from hexane. 2.6 g of rac-3β-cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinoline- 2α-Keto, m.p. = 99-101°C.

The educt rac-3-cyclopropylmethyl-4-dimethylamino-butan-2-one (compound of general formula VI) used above can be prepared by the following procedure or a procedure analogous thereto.

(i) 36.2 g of ethyl 3-oxo-butyrate was added dropwise to a solution obtained by dissolving 7 g of sodium in 160 ml of ethanol while stirring at room temperature. Thereafter 45.1 g of (bromomethyl)-cyclopropane are added and the mixture is heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, then the system was poured onto 500 ml of water and extracted three times with ether. After drying over anhydrous sodium sulfate, the solvent was evaporated and the residue was distilled. 38.9 g of ethyl 2-acetyl-cyclopropylpropionate are obtained, b.p.=35-36° C./0.3 mbar.

(ii) A solution obtained by dissolving 3.9 g of potassium hydroxide in 30 ml of water was added to a solution obtained by dissolving 11.6 g of ethyl 2-acetyl-cyclopropylpropionate at room temperature. After stirring at room temperature for 4 hours, the mixture was neutralized with about 5.2 ml of concentrated hydrochloric acid and then 5.16 g of dimethylamine-hydrochloride and 4.82 ml of a 36.5% formaldehyde solution were added. Thereafter, 5.24 ml of concentrated hydrochloric acid was added over 1 hour while stirring at room temperature and the mixture was stirred at the same temperature for 18 hours and extracted twice with diethyl ether. After drying over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by chromatography (silica gel, dichloromethane-methanol/25% ammonium hydroxide (0-10%)) and subsequent distillation (Kugelrohr). 2.9 g of rac-3-cyclopropylmethyl-4-dimethylamino-butan-2-one are obtained, b.p.=95° C./11 mbar.

Example 19

To 380mg rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2β- 2 ml of saturated hydrochloric acid in ethanol was added to a solution obtained by dissolving baseamine in 40 ml of ethanol. The mixture was stirred at room temperature for 1 hour and the solid was filtered off. Obtained 381 mgrac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-yl Amine dihydrochloride, MS (ISP) 319.5 (M+H) ⁺ .

Example 20-42

The following compounds were prepared in a similar manner to Example 19:

20.rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α- Ammonium dihydrochloride, MS (ISP) 319.5 (M+H) ⁺ .

21. rac-9,10-dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2β- Ammonium dihydrochloride, mp=282-288°C, MS (ISP) 305.4 (M+H) ⁺ .

22. rac-9,10-dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α- Ammonium dihydrochloride, mp=270-275°C, decomposition, MS (ISP) 305.3 (M+H) ⁺ .

23. rac-9,10-dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] Isoquinolin-2β-ylamine dihydrochloride as a solid, MS (ISP) 333.3 (M+H) ⁺ .

24. rac-9,10-dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] Isoquinolin-2α-ylamine dihydrochloride as a solid, MS (ISP) 333.4 (M+H) ⁺ .

25. rac-3β-(2-ethyl-butyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] Isoquinolin-2β-ylamine dihydrochloride as a solid, MS (ISP) 347.5 (M+H) ⁺ .

26. rac-3β-(2-ethyl-butyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] Isoquinolin-2α-ylamine dihydrochloride as a solid, MS (ISP) 347.4 (M+H) ⁺ .

27.rac-3β-cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline -2β-ylamine dihydrochloride, solid, MS (ISP) 317.3 (M+H) ⁺ .

28.rac-3β-cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline -2α-ylamine dihydrochloride, mp=197-210°C, MS (ISP) 317.3 (M+H) ⁺ .

29. rac-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine di Hydrochloride, mp=197-210°C, MS (ISP) 289.3 (M+H) ⁺ .

30. rac-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine dihydrochloride as a solid , MS (ISP) 259.3 (M+H) ⁺ .

31. rac-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine dihydrochloride as a solid , MS (ISP) 259.2 (M+H) ⁺ .

32. rac-3β-butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2β- Ammonium dihydrochloride, mp=116-120°C, MS (ISP) 319.5 (M+H) ⁺ .

33. rac-3β-butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α- Ammonium dihydrochloride, mp=260-265°C, MS (ISP) 319.5 (M+H) ⁺ .

34. rac-2β-amino-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-10 -Alcohol dihydrochloride, mp=295-299°C, MS (ISP) 305.4 (M+H) ⁺ .

35. rac-2α-amino-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-10 -Alcohol dihydrochloride, mp=322-324°C, MS (ISP) 305.4 (M+H) ⁺ .

36. rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2- f] Phenanthridine-8β-ylamine dihydrochloride, mp=225-233°C, MS (ISP) 373.4 (M+H) ⁺ .

37.rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2- f] Phenanthridine-8α-ylamine dihydrochloride, mp=215-222°C, MS (ISP) 373.5 (M+H) ⁺ .

38. rac-2β-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-9 -Alcohol dihydrochloride, mp=230-237°C, MS (ISP) 305.5 (M+H) ⁺ .

39. rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-9 -Alcohol dihydrochloride, mp=230-250°C, MS (ISP) 305.5 (M+H) ⁺ .

40. rac-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine di Hydrochloride, MS (ISP) 289.3 (M+H) ⁺ .

41. rac-3β-isobutyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2β -Amine dihydrochloride, MS (ISP) 319.4 (M+H) ⁺ .

42.rac-3β-isobutyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α -Amine dihydrochloride, MS (ISP) 319.4 (M+H) ⁺ .

Example 43

Treat 500 mg rac-9-benzyloxy-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1- a] A solution of isoquinolin-2-one oxime dissolved in 60 ml of ethanol was vigorously stirred at room temperature for 18 hours. The catalyst was filtered off, washed with ethanol/water (1:1) and the filtrate was evaporated. The residue was purified by chromatography (silica gel, dichloromethane-methanol/25% ammonium hydroxide (0-12%)). Obtained: (a) 0.08 g of rac-2β-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] isoquinolin-9-ol as a solid, MS (ISP) 305.4 (M+H) ⁺ ; and (b) 0.24 g of rac-2α-amino-3β-butyl-10-methoxy-1, 3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol as a solid, MS (ISP) 305.4 (M+H) ⁺ .

rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a] was prepared as described in Example 1 Isoquinolin-2-one oxime and rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]iso The educt used in Example 43 was prepared in an analogous manner to quinolin-2-ones:

rac-9-benzyloxy-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one Oxime, m.p. = 148-149°C.

rac-9-benzyloxy-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one , m.p. = 118-119°C.

Examples 44 and 45

The following compounds were prepared in a similar manner to Example 1:

44. rac-9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2- Amylamine, MS (ISP) 339.4 (M+H) ⁺ .

45. rac-2α-amino-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-8 - Alcohol as resin, MS (ISP) 305.4 (M+H) ⁺ .

The educts used in Examples 44 and 45 not yet described above (compounds of general formula II and III) can be prepared according to the following procedure or a procedure analogous thereto.

Oxime derivatives (compounds of general formula II)

rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a] as described in Example 1 above Isoquinolin-2-one oxime similar steps to prepare the following compounds:

rac-9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one oxime, m.p. = 232-234°C.

Ketone derivatives (compounds of general formula III)

rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a] as described in Example 1 above The similar steps of isoquinolin-2-ones prepare the following compounds:

rac-9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one, m.p.= 232-234°C.

3β-butyl-8-hydroxy-9-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one, m.p.=232 -234°C.

Example 46

4.82 grac-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine was dissolved The resulting mixture was stirred at reflux for 7 hours in 23 ml of 48% aqueous HBr. The mixture was cooled to 0° C. and 20% aqueous NH ₄ OH was added to reach pH = 9, followed by NaCl to saturation. The product was extracted with dichloromethane. The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was evaporated to give 4.80 g of rac-2α-amino-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[ 2,1-a]isoquinolin-9-ol as a solid, MS (ISP) 275.4 (M+H) ⁺ .

Example 47

rac-3β-butyl-9-phenylethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine disalt salt

(i) To 4.50 grac-2α-amino-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-9-alcohol To the resulting solution in 36 ml of anhydrous DMF were added Et ₃ N (12.78 ml) and di-tert-butyl dicarbonate (4.44 g). After stirring for 3 hours, water (180ml) was added and the product was extracted with 3 portions of ether. The combined organic layers were dried ( _Na2SO4 ) and _the solvent was evaporated to give a crude product which was purified by chromatography (silica gel, hexane/ethyl acetate 3:1 - pure ethyl acetate). 3.92 g of rac-(3β-butyl-9-hydroxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl) were obtained - tert-butyl carbamate as a solid, mp = 105°C.

(ii) Preparation of 100 mg of rac-(3β-butyl-9-hydroxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a] on polystyrene resin A mixture obtained by dissolving isoquinolin-2α-yl)-tert-butyl carbamate, phenylethyl alcohol (35ul) and triphenylphosphine (222mg, ~3mmol triphenylphosphine/g resin) in dichloromethane (2.6ml) and Add di-tert-butyl azodicarboxylate. The mixture was shaken for 18 hours, then the polymer was removed by filtration and washed with dichloromethane and trifluoroacetic acid (2ml) was added. After stirring _for 2 hours, the acid was neutralized by the addition of saturated aqueous _Na2CO3 . The organic layer was dried ( _MgSO4 ) and the solvent was evaporated. The product was isolated as the dihydrochloride salt by precipitation from 1.5M HCl in ethyl acetate. Obtained 83 mg of rac-3β-butyl-9-phenethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl Amine dihydrochloride, solid, MS (IPS) 379.3 (M+H) ⁺ .

Example 48-59

The following compounds were prepared in a similar manner to Example 47:

48. rac-3β-butyl-9-ethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine di Hydrochloride, as a solid, MS (ISP) 303.4 (M+H) ⁺ .

49. rac-3β-butyl-9-propoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine di Hydrochloride, as a solid, MS (ISP) 317.4 (M+H) ⁺ .

50. rac-9-butoxy-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine di Hydrochloride, as a solid, MS (ISP) 331.4 (M+H) ⁺ .

51. rac-3β-butyl-9-isobutoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine Dihydrochloride, solid, MS (ISP) 331.4 (M+H) ⁺ .

52. rac-9-benzyloxy-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine di Hydrochloride, as a solid, MS (ISP) 365.4 (M+H) ⁺ .

53. rac-3β-butyl-9-[2-(4-dimethylamino-phenyl)-ethoxy]-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[ 2,1-a]isoquinolin-2α-ylamine dihydrochloride as a solid, MS (ISP) 422.5 (M+H) ⁺ .

54. rac-4-[2-(2α-amino-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-9 -yloxy)-ethyl]-benzonitrile dihydrochloride as a solid, MS (ISP) 404.6 (M+H) ⁺ .

55.rac-3β-butyl-9-[2-(4-methyl-thiazol-5-yl)-ethoxy]-1,3,4,6,7,11bβ-hexahydro-2H-pyridine And[2,1-a]isoquinolin-2α-ylamine dihydrochloride, solid, MS (ISP) 400.6 (M+H) ⁺ .

56. rac-3β-butyl-9-(pyridin-3-ylmethoxy)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinone Phylin-2α-ylamine dihydrochloride as a solid, MS (ISP) 366.4 (M+H) ⁺ .

57. rac-3β-butyl-9-(pyridin-2-ylmethoxy)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinone Phylin-2α-ylamine trihydrochloride as a solid, MS (ISP) 366.3 (M+H) ⁺ .

58.rac-(2α-amino-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yloxy) - Ethyl acetate dihydrochloride as a solid, MS (ISP) 361.4 (M+H) ⁺ .

59.rac-3β-butyl-9-(2-morpholin-4-yl-ethoxy)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1- a] Isoquinolin-2α-ylamine dihydrochloride, solid, MS (ISP) 388.4 (M+H) ⁺ .

Example 60

rac-9,10-dimethoxy-3β-pyrrol-1-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α -Amine

(i) 2-Amino-9,10-dimethoxy-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester

3-(1-Ethoxycarbonylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propionic acid was treated with sodium acetate (9.67g, 135mmol) The resulting solution of the ethyl ester (Helv. Chim. Acta 1958, 41, 119; 17.1 g, 45.0 mmol) was dissolved in cyclohexane (340 mL) and heated on an oil bath and removed by distillation within 30 minutes. ethanol, while adding cyclohexane to keep the reaction volume constant. After cooling, the reaction mixture was neutralized with acetic acid and concentrated. The residue was dissolved in dichloromethane/water 1:1 and adjusted to pH 10 with concentrated ammonium hydroxide solution. The organic layer was separated, dried ( _MgSO4 ) and evaporated. The residue was dissolved in methanol (270 mL) and ammonium acetate (42.3 g, 548 mmol) was added. After stirring at rt for 90 min, the reaction mixture was evaporated and the residue was partitioned between dichloromethane and 1M aqueous sodium hydroxide. The organic layer was dried ( _MgSO4 ), evaporated and chromatographed ( _SiO2 , _CH2Cl2 / _MeOH / _NH4OH 97.5:2.5:0.25) to give the title compound (9.90 g, 66%). Pale yellow solid, MS (ISP) 333.2 (M+H) ⁺ .

(ii) rac-3α-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquino Phenoline-2β-carboxylate ethyl ester

Add trifluoroacetic acid (18 mL) to 2-amino-9,10-dimethoxy-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquine at 0 °C Phenyl-3-carboxylic acid ethyl ester (1.00 g, 3.01 mmol) was dissolved in tetrahydrofuran (9 mL) and after 30 min the homogeneous solution was treated with sodium borohydride (237 mg, 6.02 mmol) and stirred for a further 45 min . The reaction mixture was poured onto 2M aqueous sodium hydroxide and extracted with dichloromethane. Dry ( _MgSO4 ) and evaporate. The residue was dissolved in dichloromethane (10 mL), di-tert-butyl-dicarbonate (711 mg, 319 mmol) was added and the solution was stirred at rt for 16 hours, then evaporated. Chromatography ( _SiO2 , _CH2Cl2 / _MeOH / _NH4OH 97.5:2.5:0.25) of the residue afforded the title compound (1.14 g, 87%). Pale yellow solid, MS (ISP) 435.4 (M+H) ⁺ .

(iii) rac-(2α-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]iso Quinolin-3β-yl)-benzyl carbamate

rac-2α-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H- A solution of ethyl pyrido[2,1-a]isoquinoline-3β-carboxylate (1.00 g, 2.30 mmol) was dissolved in tetrahydrofuran (10 mL) and the resulting mixture was stirred at rt. After 16 hours, an additional portion of 1M aqueous sodium hydroxide solution (0.23 mL, 0.23 mmol) was added and stirring was continued for 4 hours. The solvent was then evaporated, the residue was suspended twice in toluene (50 mL) and concentrated to remove the remaining water azeotropically. The residue was suspended in toluene (20 mL) and treated with diphenylphosphoryl azide (669 mg, 2.30 mmol) and triethylamine (234 mg, 2.30 mmol). The reaction mixture was stirred at rt for 30 minutes, then heated at 80°C for 45 minutes, then benzyl alcohol (374 mg, 3.47 mmol) was added and the reaction mixture was heated at 100°C for 72 hours. After cooling and partitioning between dichloromethane and water, the organic layer was washed with brine, dried ( _MgSO4 ) and evaporated. Chromatography ( _SiO2 , _CH2Cl2 / _MeOH / _NH4OH 95:5:0.25) of the residue afforded the title compound (278 mg, 24%). White solid, MS (ISP) 512.5 (M+H) ⁺ .

(iv) rac-(3β-amino-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α -yl)-tert-butyl carbamate

Hydrogenation of rac-(2α-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7, A solution obtained by dissolving benzyl 11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-3β-yl)-carbamate (275 mg, 0.538 mmol) in acetic acid (10 mL). After 30 minutes, the solvent was evaporated, the residue was treated with toluene (20 mL), the suspension was concentrated and the residue was dried in vacuo to give the title compound (247 mg, about 85% purity), which was used directly in the next step. Pale yellow solid, MS (ISP) 378.4 (M+H) ⁺ .

(v) rac-(9,10-dimethoxy-3β-pyrrol-1-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]iso Quinoline-2α-yl)-tert-butyl carbamate

2,5-Dimethoxytetrahydrofuran (41 mg, 0.30 mmol) was heated to rac-(3β-amino-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H -pyrido[2,1-a]isoquinolin-2α-yl)-tert-butyl carbamate (120mg, 0.27mmol/85% purity) was dissolved in acetic acid (1.2mL, 21mmol) and pyridine (0.76mL, 9.5 mmol) in the resulting solution. The homogeneous solution was heated at 100°C for 105 min, then evaporated and the residue chromatographed ( _SiO2 , heptane/ethyl acetate gradient) to give the title compound (87mg, 75%). White solid, MS (ISP) 428.3 (M+H) ⁺ .

(vi) rac-9,10-dimethoxy-3β-pyrrol-1-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinone Phylin-2α-ylamine

rac-(9,10-dimethoxy-3β-pyrrol-1-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline -2[alpha]-yl)-tert-butyl carbamate (86 mg, 0.20 mmol) was dissolved in hydrogen chloride solution (4M in dioxane, 1 mL), stirred at rt for 1 hour and evaporated. The residue was chromatographed ( _SiO2 , _CH2Cl2 / _MeOH / _NH4OH 95:5:0.25) to afford the title compound (58 mg, 88%). White solid, MS (ISP) 328.3 (M+H) ⁺ .

Examples 61 and 62

The following compounds were prepared in a similar manner to Example 1:

61. rac-9,10-dimethoxy-3β-p-tolyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2β -Amine, yellow powder, MS (ISP) 353.3 (M+H) ⁺ .

62. rac-9,10-dimethoxy-3β-p-tolyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α -Amine, light yellow powder, MS (ISP) 353.3 (M+H) ⁺ .

The educts used in Examples 61 and 62 not yet described above (compounds of general formula II, III and VI) can be prepared according to the following procedure or a procedure analogous thereto.

Oxime derivatives (compounds of general formula II)

rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a] as described in Example 1 above Isoquinolin-2-one oxime similar steps to prepare the following compounds:

rac-9,10-dimethoxy-3β-p-tolyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one oxime, It is light yellow powder, MS(ISP)367.2(M+H) ⁺ .

Ketone derivatives (compounds of general formula III)

rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a] as described in Example 1 above The similar steps of isoquinolin-2-ones prepare the following compounds:

rac-9,10-dimethoxy-3β-p-tolyl-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one, for Off-white powder, MS(ISP)352.3(M+H) ⁺ .

Ammonium iodide derivatives (compounds of general formula V)

A mixture obtained by dissolving 4-methylphenylacetone (3.01 g), paraformaldehyde (0.489 g) and dimethylamine hydrochloride (1.49 g) in MeOH (2 ml) was stirred under reflux for 3 hours. The reaction mixture was diluted with 20 mL of water and the product was extracted with two portions of ether. After addition of 1M aqueous NaOH, the aqueous layer was extracted with two more portions of ether. The combined organic layers were dried ( _Na2SO4 ) and the solvent was evaporated to give 4-dimethylamino-3-p-tolyl-butan-2-one (compound _of general formula VI) as light yellow liquid, MS (ISP) 206.2(M+H) ⁺ . 4-Dimethylamino-3-p-tolyl-butan-2-one was dissolved in AcOEt (17ml) and iodomethane (1.46) was added. After 1 hour, the solid formed was collected by filtration, washed with AcOEt and dried in vacuo. This gave 2.61 g of trimethyl-(3-oxo-2-p-tolyl-butyl)-ammonium iodide as an off-white solid, MS (ISP) 220.3 M ⁺ .

Examples 63 and 64

(i) 21.5 mg of palladium acetate, 276 mg of sodium tert-butoxide and 23 mg of tri-tert-butylphosphine were placed in a flask, evaporated and argon gas was passed through it three times. Add 2 ml of tetrahydrofuran under argon atmosphere. To this solution was added 177 mg 4-bromoxylene and 250 mgrac-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-benzo[a] dissolved in 1 ml tetrahydrofuran Quinazin-2-ones (D. Beke, C. Szantay, Chem. Ber. 95, 2132 (1962)). The reaction was stirred overnight at room temperature under argon. The crude reaction was diluted with ether, washed with water and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel, ether) to give 92.0 mg of rac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6 , 7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one as a pale yellow solid. ¹ HNMR (CDCl ₃ ): δ=7.16-6.90 (m, 3H), 6.64 (s, 1H), 6.59 (s, 1H), 3.93-3.71 (m, 8H, 2 MeO+2H), 3.40-3.36 ( m, 1H), 3.17-2.6 (m, 7H), 2.4-2.2 (m, 6H, 2Ar- _CH3 ). MS (ISP): 366.2 (M+H) ⁺ .

(ii) To 86 mg rac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-pyrido[2.1 -a] To the yellow suspension obtained by dissolving isoquinolin-2-one in 4 ml of ethanol were added 21.2 mg of sodium acetate and 18.0 mg of hydroxylamine hydrochloride. The reaction mixture was stirred at room temperature for 4 hours. Add 4ml of water and 150mg of nickel-aluminum alloy. 0.7 ml of 32% aqueous sodium hydroxide solution was added dropwise. The mixture was stirred overnight at room temperature, filtered and the solution was extracted three times with dichloromethane. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by chromatography (silica gel, dichloromethane/methanol/saturated aqueous ammonia=97/3/0.3). Two products were obtained. They were dissolved separately in dichloromethane and saturated ethereal hydrochloride solution was added until solid precipitated.

63. rac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2, 1-a] Isoquinolin-2β-ylamine dihydrochloride

This gave 14.4 mg of the title compound as a pale yellow solid. The product elutes first during chromatography. ¹ H NMR (CDCl ₃ ): δ=7.17-6.95 (m, 3H), 6.70 (s, 1H), 6.60 (s, 1H), 3.85 (s, 3H, MeO), 3, 84 (s, 3H, MeO), 3.6-2.2 (m, 17H), 2.0-1.8 (m, 1H). MS (ISP): 367.3 (M+H) ⁺ .

64. rac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2, 1-a] Isoquinolin-2α-ylamine dihydrochloride

This gave 39.5 mg of the title compound as a pale yellow solid. Product eluting later during chromatography. ¹ H NMR (CDCl ₃ ): δ=7.15-6.99 (m, 3H), 6.75 (s, 1H), 6.60 (s, 1H), 3.85 (s, 3H, Ar-CH ₃ ), 3.83 (s, 3H , MeO), 3.4-2.9 (m, 5H), 2.7-2.2 (m, 12H). MS (ISP): 367.3 (M+H) ⁺ .

Example 65-68

The following compounds were prepared in a similar manner to Examples 63 and 64:

65. rac-9,10-dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1- a] Isoquinolin-2β-ylamine dihydrochloride.

The title compound was obtained as a pale yellow solid. The product elutes first during chromatography. ¹ H NMR (CDCl ₃ ): δ=7.29-7.24 (m, 1H), 6.84-6.74 (m, 3H), 6.70 (s, 1H), 6.60 (s, 1H), 3.94-3.82 (m, 10H, 3 MeO+1H), 3.60-2.36 (m, 10H), 2.00-1.95 (m, 1H). MS (ISP): 369.3 (M+H) ⁺ .

66. rac-9,10-dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1- a] Isoquinolin-2α-ylamine dihydrochloride.

The title compound was obtained as a light yellow solid. Product eluting later during chromatography. ¹ H NMR (CDCl ₃ ): δ=7.30-7.24 (m, 1H), 6.89-6.79 (m, 3H), 6.75 (s, 1H), 6.60 (s, 1H), 3.85-3.82 (m, 6H, 2MeO), 3.82(m, 4H, 1MeO+1H), 3.4-2.2(m, 11H). MS (ISP): 369.3 (M+H) ⁺ .

67. rac-9,10-dimethoxy-3β-pyridine-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-yl Amine dihydrochloride.

The title compound was obtained as a light yellow solid. The product elutes first during chromatography. ¹ H NMR (CDCl ₃ ): δ=8.60-8.57 (m, 1H), 7.68-7.63 (m, 1H), 7.27-7.15 (m, 2H), 6.71 (s, 1H), 6.60 (s, 1H) , 3.85-3.84 (m, 7H, 2MeO), 3.8-3.0 (m, 7H), 2.8-2.6 (m, 1H), 2.45-2.39 (m, 1H), 2-1.92 (m, 1H). MS (ISP): 340.3 (M+H) ⁺ .

68. rac-9,10-dimethoxy-3β-pyridine-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl Amine dihydrochloride.

The title compound was obtained as a light yellow solid. Product eluting later during chromatography. ¹ H NMR (CDCl ₃ ): δ=8.63-8.61 (m, 1H), 7.68-7.62 (m, 1H), 7.26-7.16 (m, 2H), 6.75 (s, 1H), 6.60 (s, 1H) , 3.87-3.80 (m, 7H), 3.5-2.5 (m, 11H). MS (ISP): 340.3 (M+H) ⁺ .

Following the same procedure as described for the preparation of rac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7, 11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one The following compounds were prepared in a similar manner:

rac-9,10-dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] Isoquinolin-2-one as light yellow solid. ¹ H NMR (CDCl ₃ ): δ=7.43-6.56 (m, 5H), 3.95-3.72 (m, 11H, 3 MeO+2H), 3.45-3.40 (m, 1H), 3.2-2.6 (m, 8H) . MS (ISP): 368.3 (M+H) ⁺ .

to give rac-9,10-dimethoxy-3β-pyridin-2-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline- 2-Keto as an orange solid. ¹ H NMR (CDCl ₃ ): δ=8.38-8.35 (m, 1H), 7.72-7.67 (m, 1H), 7.07-6.96 (m, 2H), 6.68 (s, 1H), 6.62 (s, 1H) , 3.93-3.75 (m, 8H, 2 MeO+2H), 3.65-3.60 (m, 1H), 3.40-3.26 (m, 7H). MS (ISP): 339.3 (M+H) ⁺ .

Example 69-81

The following compounds were prepared in a similar manner to Example 1:

69.rac-4-(2β-amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] isoquinolin-7β-yl)-phenol, MS (ISP) 411.5 (M+H) ⁺ .

70.rac-3β-butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]iso Quinolin-2-ylamine, MS (ISP) 333.4 (M+H) ⁺ .

71. rac-3β-butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2 , 1-a] Isoquinolin-2α-ylamine, MS (ISP) 429.6 (M+H) ⁺ .

72. rac-3β-butyl-7α-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2 , 1-a] Isoquinolin-2α-ylamine, MS (ISP) 429.6 (M+H) ⁺ .

73.rac-3β-butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H -pyrido[2,1-a]isoquinolin-2α-ylamine, MS (ISP) 455.6 (M+H) ⁺ .

74.rac-3β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1- a] Isoquinolin-2α-ylamine, MS (ISP) 347.5 (M+H) ⁺ .

75.rac-3β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1- a] Isoquinolin-2β-ylamine, MS (ISP) 347.5 (M+H) ⁺ .

76. rac-7β-butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2- f] Phenanthridine-8β-ylamine, MS (ISP) 373.5 (M+H) ⁺ .

77. rac-7β-butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα13bβ-decahydro-1H-pyrido[1,2-f] Phenanthridine-8α-ylamine, MS (ISP) 373.5 (M+H) ⁺ .

78. rac-3β-butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ - Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine, MS (ISP) 411.5 (M+H) ⁺ .

79. rac-7β-butyl-11,12-dimethoxy-13b-methyl-2,3,4,4aβ,6,7,8,9,9a,13b-decahydro-1H-pyrido [1,2-f]phenanthridin-8β-ylamine, MS (ISP) 387.4 (M+H) ⁺ .

80. rac-9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinoline-2α- Amylamine, MS (ISP) 339.3 (M+H) ⁺ .

81. rac-9,10-dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinoline-2β- Amylamine, MS (ISP) 339.4 (M+H) ⁺ .

Oxime derivatives (compounds of general formula II)

rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a] as described in Example 1 above Isoquinolin-2-one oxime similar steps to prepare the following compounds:

rac-3α-butyl-9,10-dimethoxy-7α-(4-methoxy-phenyl)-1,3,4,6,7,11bα-hexahydro-pyrido[2,1 -a] Isoquinolin-2-one oxime, MS (ISP) 439.5 (M+H) ⁺ .

rac-7β-butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα13bβ-decahydro-1H-pyrido[1,2-f]phenanthridine -8-ketoxime, MS (ISP) 439.5 (M+H) ⁺ .

rac-3-butyl-7-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6-methyl-1,3,4,6,7,11b-hexa Hydrogen-pyrido[2,1-a]isoquinolin-2-one oxime, MS (ISP) 483.5 (M+H) ⁺ .

Ketone derivatives (compounds of general formula III)

rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a] as described in Example 1 above The similar steps of isoquinolin-2-ones prepare the following compounds:

rac-3β-butyl-7β-(4-hydroxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a ] Isoquinolin-2-one, MS (ISP) 410.5 (M+H) ⁺ .

rac-3β-butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinoline-2 - Ketone, MS (ISP) 332.5 (M+H) ⁺ .

rac-3β-butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβhexahydro-pyrido[2,1-a] Isoquinolin-2-one, MS (ISP) 438.5 (M+H) ⁺ .

rac-3β-butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[ 2,1-a]isoquinolin-2-one, MS (ISP) 454.5 (M+H) ⁺ .

rac-3β-butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1 -a] Isoquinolin-2-one, MS (ISP) 424.5 (M+H) ⁺ .

rac-3β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinone Lin-2-one, MS (ISP) 346.5 (M+H) ⁺ .

rac-7-butyl-11,12-dimethoxy-1,2,3,4,4a,6,7,9,9a,13b-decahydro-pyrido[1,2-f]phenanthridine -8-one, MS (ISP) 372.5 (M+H) ⁺ .

rac-3β-butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ-hexa Hydrogen-pyrido[2,1-a]isoquinolin-2-one, MS (ISP) 467.5 (M+H) ⁺ .

rac-7β-butyl-11,12-dimethoxy-13b-methyl-2,3,4,4a,6,7,8,9,9a,13b-decahydro-1H-pyrido[1 , 2-f]phenanthridin-8-one, MS (ISP) 386.5 (M+H) ⁺ .

Synthesis of dihydroisoquinolines (compounds of general formula IV)

Similar to N. Sotomayor, E. Dominguez and E. Lete in Tetrahedron; 51; 12721 (1995).

rac-6,7-dimethoxy-4,4-dimethyl-3,4-dihydro-isoquinoline

Treat 1.0 g of 1,2,3,4-tetrahydro-6,7-dimethoxy-4,4-dimethyl-isoquinoline in 100 ml of ethanol with 2.3 g of iodine and 0.49 g of sodium acetate solution and heated at reflux for 1 hour. The reaction mixture was cooled and 30 ml of 10% sodium thiosulfate solution were added. The mixture was then diluted with water and extracted with dichloromethane (2 x 100ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the foamy residue by chromatography ( _SiO2 , dichloromethane-1% ammonia in methanol, 0-12%) afforded the title compound as a pale yellow oil (0.72 g), MS (ISP) 220.4 (M +H) ⁺ .

rac-4-(4-chloro-phenyl)-6,7-dimethoxy-3,4-dihydro-isoquinoline, MS (ISP) 302.3 (M+H) ⁺ .

rac-4-(3,4-dimethoxy-phenyl)-6,7-dimethoxy-3,4-dihydro-isoquinoline, MS (ISP) 328.4 (M+H) ⁺ .

rac-6,7-dimethoxy-4-(4-methoxy-phenyl)-3,4-dihydro-isoquinoline, MS (ISP) 298.4 (M+H) ⁺ .

rac-4α-(3,4-dimethoxy-phenyl)-6,7-dimethoxy-3α-methyl-3,4-dihydro-isoquinoline, MS (ISP) 342.3 (M +H) ⁺ .

rac-8,9-dimethoxy-10b-methyl-1,2,3,4,4a,10b-hexahydro-phenanthridine, MS (ISP) 250.4 (M+H) ⁺ .

Examples 82-85

In a similar manner to Example 1 the following enantiopure amines were obtained from the corresponding enantiopure ketones.

82. 9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine , MS (ISP) 339.3 (M+H) ⁺ .

83. 9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine , MS (ISP) 339.3 (M+H) ⁺ .

84. 9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine , MS (ISP) 339.3 (M+H) ⁺ .

85. 9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine , MS (ISP) 339.3 (M+H) ⁺ .

Ketone derivatives (compounds of general formula III)

By using Chiracel OD (20m, 25cm×5cm) to the corresponding racemic mixture rac-9,10-dimethoxy-3-phenyl-1,3,4,6,7,11b-hexahydro-pyridine Chiral separation of [2,1-a]isoquinolin-2-one, eluting with heptane/EtOH/DEA (80/20/0.01 at 80ml/min) gave (-/trans)- 9,10-Dimethoxy-3-phenyl-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one ([α] _D ²⁰ = -46.3 (c 0.28, CHCl ₃ , λ = 436nm)) and (+/trans)-9,10-dimethoxy-3-phenyl-1,3,4,6,7,11b- Hexahydro-pyrido[2,1-a]isoquinolin-2-one ([α] _D ²⁰ =+44.8 (c 0.28, CHCl ₃ , λ=436 nm)).

Example 86

By (6S)-3-butyl-6-hydroxymethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido in a similar manner to Example 1 [2,1-a]isoquinolin-2-one gives (6S)-(2-amino-3-butyl-9,10-dimethoxy-1,3,4,6,7,11b- Hexahydro-2H-pyrido[2,1-a]isoquinolin-6-yl)-methanol.

(6S)-3-Butyl-6-hydroxymethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinone Lin-2-one

(i) 1.4 g of (S)-6,7-dimethoxy-3-tert-butyldimethoxysilyloxymethyl- 3,4-dihydroisoquinoline (Y.Haraguchi, Kozima, S.Yamaguchi, R. "Asymmetric tetrahedron" (Tetrahedron Asymmetry), 1996, 7, 443) was dissolved in 8.5 ml of methanol and the resulting solution was Heated at reflux for 4 hours. After this time a further 0.7 g of (2-acetylhexyl)trimethylammonium iodide were added and the reaction mixture was stirred at reflux for a further 20 hours. The reaction mixture was cooled and treated with a solution of 0.76 g potassium hydroxide dissolved in 70 ml water. Ethanol was evaporated and the aqueous solution was extracted three times with 15 ml of dichloromethane.

The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography (silica gel, hexane/ethyl acetate 0-100%) to afford 1.95 g of (6S)-3-butyl-3-hydroxy-6-tert-butyldimethoxysilyloxy Methyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one, as diastereomers The mixture, MS (ISP) 462.5 (M+H) ⁺ .

(ii) To 0.40g (6S)-3-butyl-3-hydroxyl-6-tert-butyldimethoxy-silyloxymethyl-9,10-dimethoxy-1 at 0°C , 3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-ketone was dissolved in 13ml THF obtained solution and slowly added 1.78ml tetrabutylammonium fluoride ( 1M THF solution). The reaction mixture was stirred for 2 hours while maintaining a temperature of 0-5 °C. The reaction mixture was poured into cooled water (49ml) and then extracted twice with 30ml ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated in vacuo. Subsequent purification of the residue by chromatography (silica gel, hexane/ethyl acetate 0-70%) afforded 0.30 g of (6S)-3-butyl-6-hydroxymethyl-9,10-dimethoxy- 1,3,4,6,7,11b-Hexahydro-pyrido[2,1-a]isoquinolin-2-one, MS (ISP) 348.3 (M+H) ⁺ .

Example 87-102

The following compounds were prepared in a similar manner to Example 19:

87. rac-4-(2β-amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ]isoquinolin-7-yl)-phenol hydrochloride, MS (ISP) 411.5 (M+H) ⁺ .

88. rac-4-(2β-amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a ] Isoquinolin-7β-yl)-phenol hydrochloride, MS (ISP) 411.4 (M+H) ⁺ .

89. rac-3β-butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]iso Quinolin-2-ylamine hydrochloride, MS (ISP) 333.4 (M+H) ⁺ .

90. rac-3β-butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2 , 1-a] Isoquinolin-2α-ylamine hydrochloride, MS (ISP) 429.6 (M+H) ⁺ .

91. rac-3β-butyl-7α-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2 , 1-a] Isoquinolin-2α-ylamine hydrochloride, MS (ISP) 429.6 (M+H) ⁺ .

92. rac-3β-butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H -Pyrido[2,1-a]isoquinolin-2α-ylamine hydrochloride, MS (ISP) 455.6 (M+H) ⁺ .

93. rac-3α-butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H -Pyrido[2,1-a]isoquinolin-2β-ylamine hydrochloride, MS (ISP) 455.6 (M+H) ⁺ .

94.rac-3β-butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H -Pyrido[2,1-a]isoquinolin-2β-ylamine hydrochloride, MS (ISP) 455.6 (M+H) ⁺ .

95. rac-3β-butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H -Pyrido[2,1-a]isoquinolin-2α-ylamine hydrochloride, MS (ISP) 455.6 (M+H) ⁺ .

96. rac-3β-butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido [2,1-a]isoquinolin-2α-ylamine hydrochloride, MS (ISP) 425.5 (M+H) ⁺ .

97. rac-3β-butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido [2,1-a]isoquinolin-2β-ylamine hydrochloride, MS (ISP) 425.5 (M+H) ⁺ .

98.rac-3β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1- a] Isoquinolin-2α-ylamine hydrochloride, MS (ISP) 347.5 (M+H) ⁺ .

99.rac-3β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1- a] Isoquinolin-2β-ylamine hydrochloride, MS (ISP) 347.5 (M+H) ⁺ .

100.rac-7β-butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2- f] Phenanthridine-8β-ylamine hydrochloride, MS (ISP) 373.5 (M+H) ⁺ .

101.rac-7β-butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα13bβ-decahydro-1H-pyrido[1,2-f] Phenanthridine-8α-ylamine hydrochloride, MS (ISP) 373.5 (M+H) ⁺ .

102. rac-3β-butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ - Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine hydrochloride, MS (ISP) 411.5 (M+H) ⁺ .

Examples of Galenic Formulations

Example A

Film-coated tablets can be prepared in a conventional manner containing the following components:

Components Per Tablet

Chip

Compound of general formula (I) 10.0mg 200.0mg

Microcrystalline Cellulose 23.5mg 43.5mg

Lactose hydrate 60.0mg 70.0mg

Povidone K30 12.5mg 15.0mg

Sodium starch glycolate 12.5mg 17.0mg

Magnesium Stearate 1.5mg 4.5mg

(Tablet core weight) 120.0mg 350.0mg

film coating

Hydroxypropyl Methyl Cellulose 3.5mg 7.0mg

Macrogol 6000 0.8mg 1.6mg

Talc 1.3mg 2.6mg

Iron oxide 0.8mg 1.6mg

(yellow)

Titanium Dioxide 0.8mg 1.6mg

The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules are mixed with sodium starch glycolate and magnesium stearate and compressed into 120 or 350 mg tablet cores, respectively. The tablet cores are coated with an aqueous solution/suspension of the film coating material described above.

Example B

Capsules may be prepared in a conventional manner containing the following components:

Ingredients Per Capsule

Compound of general formula (I) 25.0mg

Lactose 150.0mg

Cornstarch 20.0mg

Talc 5.0mg

The ingredients are sieved and mixed and filled into size 2 capsules.

Example C

The injection can contain the following composition:

Compound of general formula (I) 3.0mg

Macrogol 400 150.0mg

Acetic acid Add enough to pH 5.0

Add water for injection to 1.0ml

The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 with acetic acid. The volume was adjusted to 1.0 ml by adding the balance of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Example D

Soft capsules containing the following components can be prepared in a conventional manner:

capsule contents

Compound of general formula (I) 5.0mg

Yellow Wax 8.0mg

Hydrogenated soybean oil 8.0mg

Partially hydrogenated vegetable oil 34.0mg

Soybean Oil 110.0mg

Capsule content weight 165.0mg

capsule

Gelatin 75.0mg

85% Glycerin 32.0mg

Karion 83 8.0mg (dry matter)

Titanium dioxide 0.4mg

Iron Yellow 1.1mg

The active ingredient is dissolved in a hot melt of the other ingredients and the mixture is filled into soft capsules of suitable size. Dispose of the filled softgels as usual.

Example E

Sachets may be prepared in conventional manner containing:

Compound of general formula (I) 50.0mg

Lactose fine powder 1015.0mg

Microcrystalline Cellulose (AVICEL PH 102) 1400.0mg

Sodium carboxymethylcellulose 14.0mg

Polyvinylpyrrolidone K30 10.0mg

Magnesium stearate 10.0mg

Flavor additives 1.0mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture obtained by dissolving polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavoring additives and filled into sachets.

Claims (19)

1. the compound of general formula (I) or its pharmaceutically acceptable salt:

Wherein

R ¹Be C1-C6 alkyl, aryl, heteroaryl or the C1-C6 alkyl that replaced by C3-C6 cycloalkyl, aryl or heteroaryl;

R ², R ³, and R ⁴Independent separately is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl group or C2-C6 alkenyl, and wherein C1-C6 alkyl, C1-C6 alkoxyl group and C2-C6 alkenyl are optional is replaced by C1-C6 carbalkoxy, aryl or heterocyclic radical,

R ⁵Be hydrogen, fluorine, C1-C6 alkyl or aryl;

R ⁶It is hydrogen, C1-C6 alkyl or hydroxyl-C1-C6 alkyl; Or

R ⁵And R ⁶Form 5 or 6 yuan of saturated carbon rings with the carbon atom that they connected;

R ⁷Be hydrogen, fluorine or C1-C6 alkyl;

Wherein

" aryl " is phenyl, and it is optional independently by C1-C6 alkyl, C1-C6 alkoxyl group, halogen, cyano group, azido-, amino, two-C1-C6 alkylamino or the replacement of hydroxyl list, two replacements or three replacements

" heteroaryl " is pyrryl or pyridyl, and these heteroaryls are optional to be replaced or three replacements by halogen, amino, perfluor-C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxyl group list replacement, two independently;

" heterocyclic radical " is pyridyl, thiazolyl or morpholino, and these heterocycles are optional to be replaced or three replacements by C1-C6 alkyl, C1-C6 alkoxyl group, halogen, cyano group, azido-, amino, two-C1-C6 alkylamino or hydroxyl list replacement, two independently;

But in the compound of general formula (I), do not comprise:

Rac-3 β-isobutyl--9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine dihydrochloride;

Rac-3 β-isobutyl--9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine dihydrochloride;

3-isobutyl--9,10-dimethoxy-1,3,4,6,7,11b-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2-base amine;

Rac-3 Beta-methyl-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine dihydrochloride;

Rac-3 Beta-methyl-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine dihydrochloride; With

3-ethyl-9,10-dimethoxy-1,3,4,6,7,11b-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2-base amine.

2. the compound of claim 1, wherein R ¹Be C1-C6 alkyl, aryl or the C1-C6 alkyl that replaced by C3-C6 cycloalkyl or aryl; R ², R ³, R ⁴Independent separately is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl group or C2-C6 alkenyl, and wherein C1-C6 alkyl, C1-C6 alkoxyl group and C2-C6 alkenyl are optional is replaced by C1-C6 carbalkoxy, aryl or heterocyclic radical; R ⁵And R ⁶Independently separately form 5 or 6 yuan of saturated carbon rings for hydrogen, C1-C6 alkyl, aryl or with the carbon atom that they connected, wherein " aryl " and " heterocyclic radical " such as claim 1 definition.

3. any one compound, wherein R in the claim 1 or 2 ¹Be C1-C6 alkyl, phenyl or C3-C6 cycloalkyl-C1-C6 alkyl.

4. claim 1 or 2 compound, wherein R ¹It is C1-C6 alkyl or by the C1-C6 alkyl of C3-C6 cycloalkyl substituted.

5. the compound of claim 1, wherein R ¹It is the heteroaryl residue that is selected from pyrryl and pyridyl.

6. claim 1 or 2 compound, wherein R ², R ³, R ⁴Independent separately be hydrogen, hydroxyl, C1-C6 alkoxyl group or by the C1-C6 alkoxyl group of aryl, heterocyclic radical or the replacement of C1-C6 carbalkoxy, wherein " aryl " and " heterocyclic radical " such as claim 1 definition.

7. claim 1 or 2 compound, wherein R ², R ³, R ⁴Independent separately is by phenyl or by the C1-C6 alkyl of the phenyl replacement of two-C1-C6 alkylamino or cyano group replacement.

8. claim 1 or 2 compound, wherein R ²It is the C1-C6 alkoxyl group.

9. claim 1 or 2 compound, wherein R ³Be C1-C6 alkoxyl group, hydrogen, hydroxyl or the C1-C6 alkoxyl group that replaced by aryl, heterocyclic radical or C1-C6 carbalkoxy, wherein " aryl " and " heterocyclic radical " such as claim 1 definition.

10. claim 1 or 2 compound, wherein R ³Be C1-C6 alkoxyl group, hydrogen or hydroxyl.

11. the compound of claim 1 or 2, wherein R ⁴Be C1-C6 alkoxyl group, hydrogen or hydroxyl.

12. the compound of claim 1 or 2, wherein R ⁵And R ⁶Form 6 yuan of saturated carbon rings for hydrogen or with the carbon atom that they connected.

13. the compound of claim 1 is selected from the group that following compounds is formed:

Rac-9,10-dimethoxy-3 β-propyl group-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine;

Rac-9,10-dimethoxy-3 β-(3-methyl-butyl)-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine;

Rac-3 β-cyclopropyl methyl-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine;

Rac-7 β-butyl-11,12-dimethoxy-2,3,4,4a, 6,7,8,9,9a, 13b β-decahydro-1H-pyrido [1,2-f] phenanthridines-8 beta-yl amine;

Rac-3 β-butyl-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine dihydrochloride;

Rac-9,10-dimethoxy-3 β-propyl group-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine dihydrochloride;

Rac-7 β-butyl-11,12-dimethoxy-2,3,4,4a, 6,7,8,9,9a, 13b β-decahydro-1H-pyrido [1,2-f] phenanthridines-8 beta-yl amine dihydrochloride;

Rac-2 beta-amino-3 β-butyl-10-methoxyl group-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-9-alcohol dihydrochloride;

Rac-2 alpha-amino group-3 β-butyl-10-methoxyl group-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-9-alcohol dihydrochloride;

Rac-2 beta-amino-3 β-butyl-10-methoxyl group-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-9-alcohol;

Rac-2 alpha-amino group-3 β-butyl-10-methoxyl group-1,3,4,6,7,11 β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-9-alcohol; With

Rac-9,10-dimethoxy-3 beta-phenyl-1,3,4,6,7,11 β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2-base amine.

14. the compound of claim 1 is selected from the group that following compounds is formed:

Rac-9,10-dimethoxy-3 β-(3-methyl-butyl)-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine;

Rac-7 β-butyl-11,12-dimethoxy-2,3,4,4a, 6,7,8,9,9a, 13b β-decahydro-1H-pyrido [1,2-f] phenanthridines-8 beta-yl amine;

Rac-3 β-butyl-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine dihydrochloride;

Rac-7 β-butyl-11,12-dimethoxy-2,3,4,4a, 6,7,8,9,9a, 13b β-decahydro-1H-pyrido [1,2-f] phenanthridines-8 beta-yl amine dihydrochloride;

Rac-2 alpha-amino group-3 β-butyl-10-methoxyl group-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-9-alcohol dihydrochloride;

Rac-2 alpha-amino group-3 β-butyl-10-methoxyl group-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-9-alcohol; With

Rac-9,10-dimethoxy-3 beta-phenyl-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2-base amine.

15. the compound of claim 1 is selected from the group that following compounds is formed:

Rac-9,10-dimethoxy-3 β-pyrroles-1-base-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine;

Rac-9,10-dimethoxy-3 β-p-methylphenyl-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine;

Rac-9,10-dimethoxy-3 β-p-methylphenyl-1,3,4,6,7,11b α-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine;

Rac-9,10-dimethoxy-3 β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine dihydrochloride;

Rac-9,10-dimethoxy-3 β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine dihydrochloride;

Rac-9,10-dimethoxy-3 β-(3-methoxyl group-phenyl)-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine dihydrochloride;

Rac-9,10-dimethoxy-3 β-(3-methoxyl group-phenyl)-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine dihydrochloride;

Rac-9,10-dimethoxy-3 β-pyridine-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine dihydrochloride,

Rac-9,10-dimethoxy-3 β-pyridine-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine dihydrochloride;

Rac-4-(2 beta-aminos-3 β-butyl-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-7 beta-yl)-phenol;

Rac-3 β-butyl-9,10-dimethoxy-6-methyl isophthalic acid, 3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2-base amine;

Rac-3 β-butyl-7 β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine;

Rac-3 β-butyl-7-α-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine;

Rac-3 β-butyl-7 β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine;

Rac-3 β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine;

Rac-3 β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine;

Rac-7 β-butyl-11,12-dimethoxy-2,3,4,4a β, 6,7,8,9,9a α, 13b β-decahydro-1H-pyrido [2,1-a] phenanthridines-8 beta-yl amine;

Rac-7 β-butyl-11,12-dimethoxy-2,3,4,4a β, 6,7,8,9,9a α 13b β-decahydro-1H-pyrido [1,2-f] phenanthridines-8 α-Ji amine;

Rac-3 β-butyl-7 α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6 Alpha-Methyl-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2-base amine;

Rac-7 β-butyl-11,12-dimethoxy-13b-methyl-2,3,4,4a β, 6,7,8,9,9a, 13b-decahydro-1H-pyrido [1,2-f] phenanthridines-8 beta-yl amine;

Rac-9,10-dimethoxy-3 4-benzopyrone, 3,4,6,7,11b α-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine;

Rac-9,10-dimethoxy-3 4-benzopyrone, 3,4,6,7,11b α-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine;

9,10-dimethoxy-3 4-benzopyrone, 3,4,6,7,11b α-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine;

9,10-dimethoxy-3 4-benzopyrone, 3,4,6,7,11b α-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine;

9,10-dimethoxy-3 beta-phenyl-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine;

9,10-dimethoxy-3 beta-phenyl-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine;

(6S)-(2-amino-3-butyl-9,10-dimethoxy-1,3,4,6,7,11b-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-6-yl)-methyl alcohol;

Rac-4-(2 beta-aminos-3 β-butyl-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-7-yl)-phenolate hydrochlorate;

Rac-4-(2 beta-aminos-3 β-butyl-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-7 beta-yl)-phenolate hydrochlorate;

Rac-3 β-butyl-9,10-dimethoxy-6-methyl isophthalic acid, 3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2-base amine hydrochlorate;

Rac-3 β-butyl-7 β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine hydrochlorate;

Rac-3 β-butyl-7 α-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine hydrochlorate;

Rac-3 β-butyl-7 β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine hydrochlorate;

Rac-3 α-butyl-7 β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine hydrochlorate;

Rac-3 β-butyl-7 β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine hydrochlorate;

Rac-3 β-butyl-7 α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine hydrochlorate;

Rac-3 β-butyl-9,10-dimethoxy-7 β-(4-methoxyl group-phenyl)-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine hydrochlorate;

Rac-3 β-butyl-9,10-dimethoxy-7 β-(4-methoxyl group-phenyl)-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine hydrochlorate;

Rac-3 β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 α-Ji amine hydrochlorate;

Rac-3 β-butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2 beta-yl amine hydrochlorate;

Rac-7 β-butyl-11,12-dimethoxy-2,3,4,4a β, 6,7,8,9,9a α, 13b β-decahydro-1H-pyrido [1,2-f] phenanthridines-8 beta-yl amine hydrochlorate;

Rac-7 β-butyl-11,12-dimethoxy-2,3,4,4a β, 6,7,8,9,9a α 13b β-decahydro-1H-pyrido [1,2-f] phenanthridines-8 α-Ji amine hydrochlorate; With

Rac-3 β-butyl-7 α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6 Alpha-Methyl-1,3,4,6,7,11b β-six hydrogen-2H-pyrido [2,1-a] isoquinoline 99.9-2-base amine hydrochlorate.

16. preparation is as the method for any described general formula (I) compound among the claim 1-15, this method comprises the following steps:

(a) oxime of reduction general formula (II):

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶And R ⁷As defined in claim 1;

Optional subsequently its pharmaceutically acceptable salt that changes into; Or

(b) compound of general formula (VII) and alcohol are reacted, the structural formula of its formula of (VII) compound is as follows:

R wherein ¹, R ², R ⁴, R ⁵, R ⁶And R ⁷As defined in claim 1 and P represent amino protecting group;

The structural formula of wherein said alcohol is as follows:

R-OH

Wherein R is by the C1-C6 alkyl of aryl, heterocyclic radical or the replacement of C1-C6 carbalkoxy;

Deprotection subsequently,

Wherein " aryl " and " heterocyclic radical " such as claim 1 definition.

17. pharmaceutical composition comprises compound any among the claim 1-15 and pharmaceutically acceptable carrier and/or assistant agent.

18. any one compound is used for suppressing the application of the active medicine of DPP-IV among the claim 1-15 in preparation.

19. any one compound is used for the treatment of and/or prevent diabetes, non-insulin-dependent diabetes mellitus (NIDDM), glucose tolerance reduction, intestinal disease, ulcerative colitis, Crohn's disease, hypertension, hydragog(ue) have application in the medicine of disease, obesity and/or metabolism syndrome of beneficial effect therein in preparation among the claim 1-15.